Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. METHODS: In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants. FINDINGS: 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures. INTERPRETATION: Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned. FUNDING: Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

[Why me? About risk and chance in case of illness]. / Waarom ik? Over risico en toeval bij ziekte.

In explaining why a patient has been struck with disease, health care professionals may turn to arguments from epidemiology, pointing to risk factors from lifestyle, diet, or genetics. Yet many patients build detailed narratives on why and when disease and illness overcame them. They can point to specific behaviors, of themselves or others, to stress, or fate. Such stories and health beliefs can help patients preserve mental health in the context of life-threatening diagnoses but stories can also be protective of physical health. There seems to be little room for "chance" in these narratives, which illustrates the apparent disparity between probabilistic descriptions and patients' need for explanations and meaning. Recent pleas for evidentiary pluralism and narrative-based medicine aim at closing this gap.

The prevalence of non-accidental trauma among children with polytrauma: A nationwide level-I trauma centre study.

OBJECTIVE: We aimed to investigate the prevalence and characteristics of non-accidental trauma (NAT) in children with polytrauma treated at level-I trauma centres (TC). SUMMARY OF BACKGROUND: Data 6-10% Of children who present at the emergency department with injuries, sustain polytrauma. Polytrauma may result from either accidental (AT) or NAT, i.e. inflicted or neglect. The prevalence of NAT among children with polytrauma is currently unclear. METHODS: This is a retrospective study that included children (0-18 years) with an Injury Severity Score >15, who presented at one of the 11 Level-I trauma centers (TC) in the Netherlands between January 1, 2010 and January 1, 2016. Outcomes were classified based on the conclusions of the Child Abuse and Neglect-team. Cases in which conclusions were unavailable and there was no clear accidental cause of injuries were reviewed by an expert panel. RESULTS: The study included 1623 children, 1452 (89%) were classified as AT, 171 (11%) as NAT; 39 (2,4%) inflicted and 132 (8,1%) neglect. Of pre-school aged children (<5 years) 41% sustained NAT (OR26.73, 95%CI 17.70-40.35), 35/342 (10%) inflicted and 104/342 (31%) neglect. Admission due to 'cardiopulmonary arrest' was the result of inflicted trauma (30% vs 0%,p < 0.001). NAT had a higher mortality rate (16% vs 10%, p = 0.006). Indicators of NAT were: (near-)drowning (OR10.74, 95%CI 5.94-19.41), burn (OR8.62, 95%CI 4.08-18.19) and fall from height (OR2.18, 95%CI 1.56-3.02). CONCLUSIONS: NAT was the cause of polytrauma in 11% of children in our nationwide level-I TC study; 41% of these polytrauma were the result of NAT experienced by preschool-aged children. Our data show the importance of awareness for NAT.

Clinical added value of MRI to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): study protocol for an international multicentre prospective diagnostic accuracy study.

BACKGROUND: Abdominal computed tomography (CT) is the standard imaging method for patients with suspected colorectal liver metastases (CRLM) in the diagnostic workup for surgery or thermal ablation. Diffusion-weighted and gadoxetic-acid-enhanced magnetic resonance imaging (MRI) of the liver is increasingly used to improve the detection rate and characterization of liver lesions. MRI is superior in detection and characterization of CRLM as compared to CT. However, it is unknown how MRI actually impacts patient management. The primary aim of the CAMINO study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM. The secondary objective is to identify subgroups who benefit the most from additional MRI. METHODS: In this international multicentre prospective incremental diagnostic accuracy study, 298 patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT staging will be enrolled from 17 centres across the Netherlands, Belgium, Norway, and Italy. All study participants will undergo CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. The local multidisciplinary team will provide two local therapy plans: first, based on CT-staging and second, based on both CT and MRI. The primary outcome measure is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI not visible on CT. CS-CRLM are defined as liver lesions leading to a change in local therapeutical management. If MRI detects new CRLM in segments which would have been resected in the original operative plan, these are not considered CS-CRLM. It is hypothesized that MRI will lead to the detection of CS-CRLM in ≥10% of patients which is considered the minimal clinically important difference. Furthermore, a prediction model will be developed using multivariable logistic regression modelling to evaluate the predictive value of patient, tumor and procedural variables on finding CS-CRLM on MRI. DISCUSSION: The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide the evidence required for the implementation of additional MRI in the routine work-up of patients with primary and recurrent CRLM for local therapy. TRIAL REGISTRATION: The CAMINO study was registered in the Netherlands National Trial Register under number NL8039 on September 20th 2019.

The windsor definition for hyperemesis gravidarum: A multistakeholder international consensus definition.

OBJECTIVE: To develop an international definition for hyperemesis gravidarum to assist in clinical diagnosis and harmonize hyperemesis gravidarum definition for study populations. STUDY DESIGN: A mixed-methods approach was used to identify potential hyperemesis gravidarum definition criteria (i.e. systematic review, semi-structured interviews and closed group sessions with patients and Project Steering Committee input). To reach consensus on the definition we used a web-based Delphi survey with two rounds, followed by a face-to-face consensus development meeting, held in Windsor UK, and a web-based consultation round, in which the provisional hyperemesis gravidarum definition was fed back to the stakeholders. Four stakeholder groups were identified 1) researchers; 2) women with lived experience of hyperemesis gravidarum and their families; 3) obstetric health professionals (obstetricians, gynecologists, midwives); and 4) other health professionals involved in care for women with hyperemesis gravidarum (general practitioners, dieticians, nurses). To reflect the opinions of the international community, stakeholders from countries in all global regions were invited to participate. RESULTS: Twenty-one identified potential criteria entered the Delphi survey. Of the 277 stakeholders invited, 178 completed round one, and 125 (70%) also completed round two. Twenty stakeholders attended the consensus development meeting, representing all stakeholder groups. The consultation round was completed by 96 (54%) stakeholders, of which 92% agreed with the definition as presented. The consensus definition for hyperemesis gravidarum consisted of: start of symptoms in early pregnancy (before 16 weeks gestational age); nausea and vomiting, at least one of which severe; inability to eat and/or drink normally; strongly limits daily living activities. Signs of dehydration were deemed contributory for the definition for hyperemesis gravidarum. CONCLUSIONS: The proposed definition for hyperemesis gravidarum will help clinical studies to achieve more uniformity, and ultimately increasing the value of evidence to inform patient care.

Discriminating complicated from uncomplicated appendicitis by ultrasound imaging, computed tomography or magnetic resonance imaging: systematic review and meta-analysis of diagnostic accuracy.

BACKGROUND: Discriminating complicated from uncomplicated appendicitis is crucial. Patients with suspected complicated appendicitis are best treated by emergency surgery, whereas those with uncomplicated appendicitis may be treated with antibiotics alone. This study aimed to obtain summary estimates of the accuracy of ultrasound imaging, CT and MRI in discriminating complicated from uncomplicated appendicitis. METHODS: A systematic literature review was conducted by an electronic search in PubMed, Embase and the Cochrane Library for studies describing the diagnostic accuracy of complicated versus uncomplicated appendicitis. Studies were included if the population comprised adults, and surgery or pathology was used as a reference standard. Risk of bias and applicability were assessed with QUADAS-2. Bivariable logitnormal random-effect models were used to estimate mean sensitivity and specificity. RESULTS: Two studies reporting on ultrasound imaging, 11 studies on CT, one on MRI, and one on ultrasonography with conditional CT were included. Summary estimates for sensitivity and specificity in detecting complicated appendicitis could be calculated only for CT, because of lack of data for the other imaging modalities. For CT, mean sensitivity was 78 (95 per cent c.i. 64 to 88) per cent, and mean specificity was 91 (85 to 99) per cent. At a median prevalence of 25 per cent, the positive predictive value of CT for complicated appendicitis would be 74 per cent and its negative predictive value 93 per cent. CONCLUSION: Ultrasound imaging, CT and MRI have limitations in discriminating between complicated and uncomplicated appendicitis. Although CT has far from perfect sensitivity, its negative predictive value for complicated appendicitis is high.

Planned Cesarean or planned vaginal delivery for twins: secondary analysis of randomized controlled trial.

OBJECTIVE: To evaluate whether there is a differential benefit of planned Cesarean delivery (CD) over planned vaginal delivery (VD) in women with a twin pregnancy and the first twin in cephalic presentation, depending on prespecified baseline maternal and pregnancy characteristics, and/or gestational age (GA) at delivery. METHODS: This was a secondary analysis of the Twin Birth Study, which included 2804 women with a twin pregnancy and the first twin (Twin A) in cephalic presentation between 32 + 0 and 38 + 6 weeks' gestation at 106 centers in 25 countries. Women were assigned randomly to either planned CD or planned VD. The main outcome measure was composite adverse perinatal outcome, defined as the occurrence of perinatal mortality or serious neonatal morbidity in at least one twin. The baseline maternal and pregnancy characteristics (markers) considered were maternal age, parity, history of CD, use of antenatal corticosteroids, estimated fetal weight (EFW) of Twin A, EFW of Twin B, > 25% difference in EFW between the twins, presentation of Twin B, chorionicity on ultrasound, method of conception, complications of pregnancy, ruptured membranes at randomization and GA at randomization. Separate logistic regression models were developed for each marker in order to model composite adverse perinatal outcome as a function of the specific marker, planned delivery mode and the interaction between these two terms. In addition, multivariable logistic regression analysis with backward variable elimination was performed separately in each arm of the trial. The association between planned mode of delivery and composite adverse perinatal outcome, according to GA at delivery, was assessed using logistic regression analysis. RESULTS: Of the 2804 women initially randomized, 1391 were included in each study arm. None of the studied baseline markers was associated with a differential benefit of planned CD over planned VD in the rate of composite adverse perinatal outcome. GA at delivery was associated differentially with composite adverse perinatal outcome in the treatment arms (P for interaction < 0.001). Among pregnancies delivered at 32 + 0 to 36 + 6 weeks, there was a trend towards a lower rate of composite adverse perinatal outcome in those in the planned-VD group compared with those in planned-CD group (29 (2.2%) vs 48 (3.6%) cases; odds ratio (OR) 0.62 (95% CI, 0.37-1.03)). In pregnancies delivered at or after 37 + 0 weeks, planned VD was associated with a significantly higher rate of composite adverse perinatal outcome, as compared with planned CD (23 (1.5%) vs 10 (0.7%) cases; OR, 2.25 (95% CI, 1.06-4.77)). CONCLUSION: The perinatal outcome of twin pregnancies with the first twin in cephalic presentation may differ depending on GA at delivery and planned mode of delivery. At 32-37 weeks, planned VD seems to be favorable, while, from around 37 weeks onwards, planned CD might be safer. The absolute risks of adverse perinatal outcomes at term are low and must be weighed against the increased maternal risks associated with planned CD. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Systematic review of reporting benefits and harms of surgical interventions in randomized clinical trials.

BACKGROUND: Standardized reporting methods facilitate comparisons between studies. Reporting of data on benefits and harms of treatments in surgical RCTs should support clinical decision-making. Correct and complete reporting of the outcomes of clinical trials is mandatory to appreciate available evidence and to inform patients properly before asking informed consent. METHODS: RCTs published between January 2005 and January 2017 in 15 leading journals comparing a surgical treatment with any other treatment were reviewed systematically. The CONSORT checklist, including the extension for harms, was used to appraise the publications. Beneficial and harmful treatment outcomes, their definitions and their precision measures were extracted. RESULTS: Of 1200 RCTs screened, 88 trials were included. For the differences in effect size of beneficial outcomes, 68 per cent of the trials reported a P value only but not a 95 per cent confidence interval. For harmful effects, this was 67 per cent. Only five of the 88 trials (6 per cent) reported a number needed to treat, and no study a number needed to harm. Only 61 per cent of the trials reported on both the beneficial and harmful outcomes of the intervention studied in the same paper. CONCLUSION: Despite CONSORT guidelines, current reporting of benefits and harms in surgical trials does not facilitate clear communication of treatment outcomes with patients. Researchers, reviewers and journal editors should ensure proper reporting of treatment benefits and harms in trials.

ANTECEDENTES: Los métodos para la estandarización en la descripción de los resultados facilitan la comparación entre estudios. La toma de decisiones clínicas debe estar respaldada por los resultados que se obtienen en los ensayos clínicos aleatorizados (randomized clinical trials, RCTs) quirúrgicos sobre los efectos beneficiosos y nocivos de los tratamientos. Es obligado que la descripción de los resultados de los ensayos clínicos sea correcta y completa a fin de estimar la evidencia disponible y poder informar a los pacientes de forma adecuada antes de solicitar el consentimiento informado. MÉTODOS: Se revisaron de forma sistemática los RCTs publicados entre enero de 2005 y enero de 2017 en las 15 revistas principales en los que se comparaba un tratamiento quirúrgico con cualquier otro. Para evaluar las publicaciones, se utilizó la guía de comprobación del CONsolidated Standard of Reporting Trials (CONSORT), haciéndola extensiva también a los efectos nocivos. Se obtuvieron los resultados sobre los efectos beneficiosos y nocivos del tratamiento, sus definiciones y sus medidas de precisión. RESULTADOS: De 1.200 RCTs seleccionados, se incluyeron 88 ensayos. Para comparar las diferencias de los efectos beneficiosos de los resultados, en el 68% de los ensayos se aportó sólo un valor de la P pero no el intervalo de confianza del 95%. Para efectos nocivos, el porcentaje fue del 67%. En sólo 5 de 88 ensayos (6%) se informó del número de pacientes que es necesario tratar (number needed to treat, NNT), y en ningún estudio se precisó el número de pacientes que es necesario para perjudicar (number needed to harm, NNH). En sólo el 61% de los ensayos se informó de los resultados beneficiosos y nocivos de la intervención analizada en el mismo artículo. CONCLUSIÓN: A pesar de la guía CONSORT, la descripción actual de los efectos beneficiosos y nocivos en los ensayos quirúrgicos no permite obtener una clara información del resultado del tratamiento obtenido en los pacientes. Los investigadores, los revisores y los editores de las revistas deben garantizar una descripción adecuada los beneficios y efectos nocivos del tratamiento en los ensayos clínicos.

Relationship between type of unprovoked venous thromboembolism and cancer location: An individual patient data meta-analysis.

BACKGROUND: Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep vein thrombosis [DVT], pulmonary embolism [PE] or both) and the anatomical relationship between occult cancer and VTE. METHODS: Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations. RESULTS: A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79). CONCLUSION: The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.

Natural conception rates in couples with unexplained or mild male subfertility scheduled for fertility treatment: a secondary analysis of a randomized controlled trial.

STUDY QUESTION: What is the natural conception rate over the course of 12 months in couples with unexplained or mild male subfertility who are scheduled for fertility treatment and have a predicted unfavourable prognosis for natural conception? SUMMARY ANSWER: The natural conception rate over the course of 12 months in couples who were allocated to treatment was estimated to be 24.5% (95% CI: 20-29%). WHAT IS KNOWN ALREADY: After starting treatment, couples often perceive unsuccessful cycles as evidence of definitive failure even though they are still able to conceive naturally in between and after treatment. The magnitude of the natural conception rate for couples who chose to commence treatment is unknown, as is whether the calculated prognosis before commencing treatment is still applicable. STUDY DESIGN, SIZE, DURATION: We performed a secondary analysis of a randomized controlled trial including couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception. Couples were allocated to either three cycles IVF with single embryo transfer (SET), six cycles of IVF in a modified natural cycle (MNC) or six cycles of IUI with controlled ovarian hyperstimulation (IUI-COH). The detailed data collection in this trial allowed us to study the conception rates in periods that couples were not receiving treatment. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We split the dataset into periods during which couples were treated and periods during which they were not treated. Couples could conceive naturally in the periods before, in between and after treatment cycles. The outcome was ongoing pregnancy, thus natural conception rate refers to natural conception leading to ongoing pregnancy. We performed a Cox proportional hazards analysis with female age, duration of subfertility and a time-varying covariate with four categories: IVF-SET, IVF-MNC, IUI-COH and no treatment. We used this Cox model to estimate the natural conception rate over 12 months of no treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 602 included couples, there were 342 ongoing pregnancies, of which 77 (23%) resulted from natural conception. The estimated natural conception rate over 12 months was 24.5% (95% CI: 20-29%) on cohort level. Estimated rates for female age varying between 18 and 38 years and duration of subfertility between 1 and 3 years ranged from 22 to 35%. LIMITATIONS, REASONS FOR CAUTION: We considered couples at risk for natural conception when not receiving treatment, whereas they might not have had periovulatory sexual intercourse. As couples were scheduled for treatment, it is possible that these couples were less inclined to try to conceive naturally, potentially leading to an underestimation of their natural conception rate if they kept trying to conceive. WIDER IMPLICATIONS OF THE FINDINGS: Couples with unexplained subfertility who are about to start fertility treatment, still have about a one in four chance of ongoing pregnancy due to natural conception over 12 months. This information can add to the counselling of couples who commenced fertility treatment after failed cycles and to emphasize not to cease their natural attempts. STUDY FUNDING/COMPETING INTEREST(S): The INeS trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch association of health care insurers (09-003). The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. No other potential conflicts of interest reported. TRIAL REGISTRATION NUMBER: The INeS trial was registered at the Dutch trial registry (NTR 939).

Cost-effectiveness of diagnostic testing strategies including cervical-length measurement and fibronectin testing in women with symptoms of preterm labor.

OBJECTIVE: To evaluate the cost-effectiveness of combining cervical-length (CL) measurement and fetal fibronectin (fFN) testing in women with symptoms of preterm labor between 24 and 34 weeks' gestation. METHODS: This was a model-based cost-effectiveness analysis evaluating seven test-treatment strategies based on CL measurement and/or fFN testing in women with symptoms of preterm labor from a societal perspective, in which neonatal outcomes and costs were weighted. Estimates of disease prevalence, test accuracy and costs were based on two recently performed nationwide cohort studies in The Netherlands. RESULTS: Strategies using fFN testing and CL measurement separately to predict preterm delivery are associated with higher costs and incidence of adverse neonatal outcomes compared with strategies that combine both tests. Additional fFN testing when CL is 15-30 mm was considered cost effective, leading to a cost saving of €3919 per woman when compared with a treat-all strategy, with a small deterioration in neonatal health outcomes, namely one additional perinatal death and 21 adverse outcomes per 10 000 women with signs of preterm labor (incremental cost-effectiveness ratios €39 million and €1.9 million, respectively). Implementing this strategy in The Netherlands, a country with about 180 000 deliveries annually, could lead to an annual cost saving of between €2.4 million and €7.6 million, with only a small deterioration in neonatal health outcomes. CONCLUSION: In women with symptoms of preterm labor at 24-34 weeks' gestation, performing additional fFN testing when CL is between 15 and 30 mm is a viable and cost-saving strategy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Evaluation of an online family history tool for identifying hereditary and familial colorectal cancer.

Identifying a hereditary colorectal cancer (CRC) syndrome or familial CRC (FCC) in a CRC patient may enable the patient and relatives to enroll in surveillance protocols. As these individuals are insufficiently recognized, we evaluated an online family history tool, consisting of a patient-administered family history questionnaire and an automated genetic referral recommendation, to facilitate the identification of patients with hereditary CRC or FCC. Between 2015 and 2016, all newly diagnosed CRC patients in five Dutch outpatient clinics, were included in a trial with a stepped-wedge design, when first visiting the clinic. Each hospital continued standard procedures for identifying patients at risk (control strategy) and then, after a predetermined period, switched to offering the family history tool to included patients (intervention strategy). After considering the tool-based recommendation, the health care provider could decide on and arrange the referral. Primary outcome was the relative number of CRC patients who received screening or surveillance recommendations for themselves or relatives because of hereditary CRC or FCC, provided by genetic counseling. The intervention effect was evaluated using a logit-linear model. With the tool, 46/489 (9.4%) patients received a screening or surveillance recommendation, compared to 35/292 (12.0%) in the control group. In the intention-to-treat-analysis, accounting for time trends and hospital effects, this difference was not statistically significant (p = 0.58). A family history tool does not necessarily assist in increasing the number of CRC patients and relatives enrolled in screening or surveillance recommendations for hereditary CRC or FCC. Other interventions should be considered.

Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta-analysis.

OBJECTIVE: Doppler ultrasonographic assessment of the cerebroplacental ratio (CPR) and middle cerebral artery (MCA) is widely used as an adjunct to umbilical artery (UA) Doppler to identify fetuses at risk of adverse perinatal outcome. However, reported estimates of its accuracy vary considerably. The aim of this study was to review systematically the prognostic accuracies of CPR and MCA Doppler in predicting adverse perinatal outcome, and to compare these with UA Doppler, in order to identify whether CPR and MCA Doppler evaluation are of added value to UA Doppler. METHODS: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, from inception to June 2016, for studies on the prognostic accuracy of UA Doppler compared with CPR and/or MCA Doppler in the prediction of adverse perinatal outcome in women with a singleton pregnancy of any risk profile. Risk of bias and concerns about applicability were assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool. Meta-analysis was performed for multiple adverse perinatal outcomes. Using hierarchal summary receiver-operating characteristics meta-regression models, the prognostic accuracy of CPR vs MCA Doppler was compared indirectly, and CPR and MCA Doppler vs UA Doppler compared directly. RESULTS: The search identified 4693 articles, of which 128 studies (involving 47 748 women) were included. Risk of bias or suboptimal reporting was detected in 120/128 studies (94%) and substantial heterogeneity was found, which limited subgroup analyses for fetal growth and gestational age. A large variation was observed in reported sensitivities and specificities, and in thresholds used. CPR outperformed UA Doppler in the prediction of composite adverse outcome (as defined in the included studies) (P < 0.001) and emergency delivery for fetal distress (P = 0.003), but was comparable to UA Doppler for the other outcomes. MCA Doppler performed significantly worse than did UA Doppler in the prediction of low Apgar score (P = 0.017) and emergency delivery for fetal distress (P = 0.034). CPR outperformed MCA Doppler in the prediction of composite adverse outcome (P < 0.001) and emergency delivery for fetal distress (P = 0.013). CONCLUSION: Calculating the CPR with MCA Doppler can add value to UA Doppler assessment in the prediction of adverse perinatal outcome in women with a singleton pregnancy. However, it is unclear to which subgroup of pregnant women this applies. The effectiveness of the CPR in guiding clinical management needs to be evaluated in clinical trials. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

[A fact-free medicine? Report by Dutch Council for Public Health and Society is slap in the face]. / Een feitenvrije geneeskunde?

A recently released report by the Dutch Council for Public Health and Society ('Raad voor Volksgezondheid en Samenleving') is subtitled "About the illusion of evidence-based practice in healthcare". The author argues that this report is a sign of the times, a period of "post-truth medicine" and "alternative facts", in which "science offers nothing but a reduction". Although the report rightly - but superfluously - argues that having an evidence base is insufficient for delivering quality care (no decisions without considering context), its depiction of the illusory nature of evidence-based practice represents a brutal slap in the face of all those who turn to sound clinical and biomedical research to back up or refute claims about the effectiveness of healthcare interventions.

IVF or IUI as first-line treatment in unexplained subfertility: the conundrum of treatment selection markers.

STUDY QUESTION: Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)? SUMMARY ANSWER: We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility. WHAT IS KNOWN ALREADY: A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI. STUDY DESIGN, SIZE, DURATION: We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples). PARTICIPANTS/MATERIALS, SETTING, METHODS: We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1. MAIN RESULTS AND THE ROLE OF CHANCE: None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10). LIMITATIONS, REASONS FOR CAUTION: Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations. WIDER IMPLICATIONS OF THE FINDINGS: We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered at the Dutch trial registry (NTR939).

Fertility and obstetric outcomes after curettage versus expectant management in randomised and non-randomised women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage.

OBJECTIVE: To assess fertility and obstetric outcomes in women treated with curettage or undergoing expectant management for an incomplete miscarriage after misoprostol treatment. STUDY DESIGN: Between June 2012 and July 2014, we conducted a multicentre randomised clinical trial (RCT) with a parallel cohort study for non-randomised women, treated according to their preference. In the RCT 30 women were allocated curettage and 29 expectant management. In the cohort 197 women participated; 65 underwent curettage and 132 women underwent expectant management. Primary outcome was curation, defined as either an empty uterus on sonography at six weeks or an uneventful clinical follow-up. We used questionnaires to assess fertility and obstetric outcome of the first new pregnancy subsequent to study enrolment. RESULTS: Curation was seen in 91/95 women treated with curettage (95.8%) versus 134/161 women managed expectantly (83.2%) (p=0.003). The response rate was 211/255 (82%). In 198 women pursuing a new pregnancy, conception rates were 92% (67/73) in the curettage group versus 96% (120/125) in the expectant management group (OR 0.96, 95% CI 0.89;1.03, p=0.34), with ongoing pregnancy rates of 87% (58/67) versus 78% (94/120), respectively (OR 1.12, 95% CI 0.99;1.28, p=0.226). Preterm birth rates were 1/46 in the curettage group versus 8/81 in the expectant management group (OR 0.22, 95% CI 0.03;1.71 P=0.15). Caesarean section rates were 23% and 24% for women in the curettage group and expectant management group respectively. CONCLUSION: In women with an incomplete evacuation of the uterus after misoprostol treatment, curettage and expectant management does not lead to different fertility and pregnancy outcomes, as compared to expectant management.

[On the timing of randomised studies: the sooner initiated, the better?] / Over de timing van gerandomiseerde trials.

The study design for randomised double-blind studies is powerful. Randomisation and blinding ensure that the groups that are compared are truly exchangeable. Any differences in health outcomes can be attributed rightfully to the one aspect on which the study groups differ: the treatment. In this commentary, we argue that the use of this powerful study design at the wrong moment can lead to undesirable situations.

The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism: an individual patient data meta-analysis.

Essentials Evidence for the simplified Wells rule in ruling out acute pulmonary embolism (PE) is scarce. This was a post-hoc analysis on data from 6 studies comprising 7268 patients with suspected PE. The simplified Wells rule combined with age-adjusted D-dimer testing may safely rule out PE. Given its ease of use, the simplified Wells rule is to be preferred over the original Wells rule. SUMMARY: Background The Wells score and D-dimer testing can safely rule out pulmonary embolism (PE). A simplification of the Wells score has been proposed to improve clinical applicability, but evidence on its performance is scarce. Objectives To compare the performances of the original and simplified Wells scores alone and in combination with age-adjusted D-dimer testing. Methods Individual patient data from 7268 patients with suspected PE enrolled in six management studies were used to evaluate the discriminatory performances of the original and simplified Wells scores. The efficiency and failure rate of the dichotomized original and simplified scores combined with age-adjusted D-dimer testing were compared by use of a one-stage random effects meta-analysis. Efficiency was defined as the proportion of patients in whom PE could be considered to be excluded on the basis of a 'PE unlikely' Wells score and a negative age-adjusted D-dimer test result. Failure rate was defined as the proportion of patients with symptomatic venous thromboembolism during a 3-month follow-up. Results The discriminatory performances of the original and simplified Wells scores were comparable (c-statistic 0.73 [95% confidence interval (CI) 0.72-0.75] versus 0.72 [95% CI 0.70-0.73]). When combined with age-adjusted D-dimer testing, the original and simplified Wells rules had comparable efficiency (3% [95% CI 25-42%] versus 30% [95% CI 21-40%]) and failure rates (0.9% [95% CI 0.6-1.5%] versus 0.8% [95% CI 0.5-1.3%]). Conclusion The original and simplified Wells rules combined with age-adjusted D-dimer testing have similar performances in ruling out PE. Given its ease of use in clinical practice, the simplified Wells rule is to be preferred.

Prediction of disease-free survival using relative change in FDG-uptake early during neoadjuvant chemoradiotherapy for potentially curable esophageal cancer: A prospective cohort study.

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been investigated as a tool for monitoring response to neoadjuvant chemo- and chemoradiotherapy (CT and CRT, respectively) and as a predictor for survival in patients with esophageal cancer. In contrast to patients who undergo neoadjuvant CT, it is not known whether patients who are clinically identified as responders after neoadjuvant CRT show better disease-free survival (DFS) than patients identified as nonresponders. The aim of the study was to determine the predictive value of FDG-uptake measured prior to and early during neoadjuvant CRT. Patients treated with neoadjuvant CRT between 2004 and 2009 within a randomized trial were included. FDG-uptake was measured at baseline and after 14 days of CRT. According to the PERCIST-criteria, patients were allocated to have metabolic response, stable disease, or progression. Patients were followed until recurrence of disease or death. The predictive value of FDG-PET was determined with univariable and multivariable analysis in patients who underwent potentially curative surgery. One-hundred and six patients were included in the analysis. Minimal follow-up for surviving patients was 60 months. No significant differences in DFS were found between patients with metabolic response, stable disease, or progression, with 5-year DFS rates of 66%, 53%, and 67%, respectively (P = 0.39). Relative change in FDG uptake after 14 days of CRT is not associated with DFS in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy followed by surgery. These measurements should not be used for prognostication in this specific group of patients.